The present invention relates to an apparatus and process for selecting and positioning particles. More particularly, the invention relates to an apparatus and process for selecting and arraying particles for a combinatorial chemistry multiple screening process.
In experimental reaction systems, each potential combination of reactants, catalysts and conditions must be evaluated in a manner that provides correlation to performance in a production scale reactor. Since about 1970, combinatorial organic synthesis (COS) has provided an important tool to address the requirements of experimental systems. COS is a systematic and repetitive synthesis that uses sets of chemical xe2x80x9cbuilding blocksxe2x80x9d to form a diverse set of molecular entities. As with traditional research, COS relies on organic synthesis methodology. However instead of synthesizing a single compound, COS exploits automation and miniaturization to synthesize large libraries of compounds; a procedure that can involve successive stages, each of which produces a chemical modification of an existing molecule of a preceding stage. The synthesis produces large numbers of diverse compounds, which can be screened for various activities.
In a typical approach to COS, arrayed, spatially addressable building blocks are reacted systematically on particle supports. The particles are distributed into a two-dimensional array so that each variant in a combinatorial library can be identified by its position in the array. The array can consist of a set of plates, each having rows and columns of wells, with one particle, or some other predetermined number of particles contained in each well. The particles are typically made of polystyrene. They serve as substrates for different compounds produced in the process of split and combine synthesis. Ultimately, synthesized compounds are stripped from the particles and tested for activity. The identity of an active compound can be determined by spectrographic analysis in the light of the information available concerning the reaction histories of the particles.
Typically, the particles are arrayed in columns and rows on plates so that they are geometrically compatible with screening systems. For example 8xc3x9712 arrays or other formats such as 384- or 896-well configurations are common. The particles are spherical and of extremely small size, e.g. 300 mm in diameter. Consequently, they are difficult to handle. It is very difficult to separate a single particle from a mixture of particles. Still another problem encountered in particle arraying is that the particles tend to be fragile and are prone to crumbling when mechanically agitated. Current processes of arraying particles include manual picking and hydrodynamic sorting in which particles are allowed to flow though an aperture. Manual picking is slow and tedious. A hydrodynamic method is slow and the equipment used is prone to clogging.
There remains a long-felt, yet unsolved need for a simple, rapid and reliable process and apparatus for selecting and positioning particles, particularly combinatorial processing particles that can reliably deliver a single particle to each point in an array.
Accordingly, the present invention provides an apparatus and process for selecting and positioning particles that meet this need. In an exemplary embodiment, the apparatus comprises a hollow tubular body (a) of a cross-section size larger than the diameter of any single particle but smaller than twice the diameter to accommodate passage of a single particle at a time through the hollow tubular body and (b) of a length to accommodate a predetermined number of particles. The apparatus includes an obstruction within the body that permits passage of fluid but prevents passage of a particle. The apparatus also includes a force applicator at one end of the tubular body to apply a force to draw a flow of fluid into the hollow tubular body with particles along a length of the body up to the obstruction and to maintain the force so as to retain the particles within the body while transporting the retained particles to a location.
In another embodiment, the invention also relates to a process for selecting particles, comprising applying a force to draw a flow of fluid with suspended particles into an end of a hollow tubular body and through the body and impeding the flow in a manner so as to permit fluid to continue to flow while retaining particles within the body at a predetermined point so as to load the body with a selection of particles.
In an alternative embodiment, the invention also relates to a process for selecting and positioning particles. According to the process, a suspension comprising a mixture of substantially uniform sized particles is established in a fluid. A hollow tubular element is introduced into the suspension. The element comprises (i) a hollow tubular body (a) of a cross-section size larger than the diameter of any single particle but smaller than twice the diameter to accommodate passage of a single particle at a time through the hollow tubular body and (b) of a length to accommodate a predetermined number of particles and (ii) an obstruction within the body that permits passage of fluid but prevents passage of a particle. A force is applied to draw a flow of fluid into an end of the element to fill the hollow tubular body with particles along a length of the body to the obstruction. The force is maintained so as to retain the particles within the body while transporting the retained particles to a location. The retained particles are deposited at the location by releasing the force.